Diagnostic Value of Copeptin in Patients with Suspected Pulmonary Embolism in Emergency Departments.

Background: Pulmonary thromboembolism (PTE) is a serious and life-threatening condition. Diagnosis of PTE can be challenging in emergency departments, as there is no absolutely reliable biomarker for the diagnosis of PTE. Copeptin (COP) is a new biomarker, which may be valuable in the diagnosis of PTE; however, its role has not been well studied. In this study, we aimed to investigate the diagnostic value of COP in the diagnosis of PTE. Materials and Methods: This study was carried out on 102 patients suspected of PTE. The serum levels of D-dimer and COP were measured, and diagnosis of PTE was confirmed by CT angiography. Next, the prognostic value of D-dimer and COP was examined. Results: The area under the curve (AUC) of D-dimer was 0.581 with a standard error (SE) of 0.07 (P=0.34). Estimation of the validity of D-dimer showed that it is a highly sensitive (100%), but poorly specific (15.8%) test. Evaluation of the predictive value of this test showed that it has a positive predictive value of 20% and a negative predictive value of 100%. The AUC of COP was 0.423 with SE of 0.1 (P=0.44). Measurement of the validity of COP test showed that it is a poorly sensitive (50%) and specific (22.9%) test. Conclusion: COP is a new cardiovascular biomarker. However, the present findings did not confirm the prognostic value of this biomarker for the diagnosis of PTE.


INTRODUCTION
Pulmonary thromboembolism (PTE) is an important clinical disease, which may be life-threatening, especially if it is not diagnosed or treated properly (1). PTE is a common emergency condition that can affect a large number of people (2). It presents with a wide range of clinical manifestations, ranging from chest pain and hypoxia to severe cardiovascular collapse (3). These clinical manifestations are non-specific, which make the early diagnosis of PTE difficult in many cases (2). On the other hand, undiagnosed PTE is a condition that can be extremely life-threatening, as a large number of PTErelated mortalities occur in the first hours of hospital admission (4).
Today, diagnosis of PTE is mainly based on radiological and laboratory studies (2). Computed tomography pulmonary angiography (CTPA) and ventilation-perfusion scan (VQ scan) are two common modalities, which are widely used to diagnose PTE. However, they have major limitations in the diagnosis of PTE. Although CTPA is a valuable diagnostic test, which can reliably detect or rule out PTE, the negative predictive There is no reliable biomarker for the diagnosis of PTE.
Today, D-dimer is used for the diagnosis of PTE.
Nevertheless, the positive predictive value (PPV) of Ddimer is low, which makes it a diagnostic test with low accuracy for the diagnosis of PTE (5,7). Despite the availability of advanced technologies and new diagnostic tools, many patients with PTE remain undiagnosed or untreated worldwide (1,5). Therefore, new diagnostic biomarkers are needed to promote rapid and accurate diagnosis of PTE.
Copeptin (COP) is the measurable C-terminal portion of provasopressin, which has been reported to have a prognostic value in many cardiopulmonary diseases (8).
Evidence suggests that measurement of COP level may be a biomarker for PTE. To date, PTE has not been widely studied, and the prognostic value of COP has not been confirmed (2). Further studies are required to confirm the prognostic value of COP as a reliable diagnostic test in the diagnosis of PTE.
In this study, we aimed to investigate the correlation between COP and PTE and to determine the validity of COP in the diagnosis of PTE.

MATERIALS AND METHODS
This cross-sectional study was conducted on 102 suspected PTE patients, who were referred to hospitals affiliated to Isfahan University of Medical Sciences from January 2016 to April 2017. The selected patients were admitted to the emergency department (ED) with dyspnea and were suspected of PTE. The inclusion criteria were as follows: age >18 years; dyspnea; glomerular filtration rate (GFR) >60 mL/min/1.73 m 2 ; and lack of hypersensitivity to dye agents. On the other hand, the exclusion criteria were as follows: use of anticoagulants; patient's death before the diagnostic tests; and unwillingness of the patient's physician to allow participation in the study.
We diagnosed acute PTE based on the findings of CTPA as a standard diagnostic test. Patients with a high probability of PTE (Wells score ≥6) and those with low to moderate probability of PTE (Wells score <6) and positive D-dimer were investigated by CTPA. Venous blood samples were collected for the measurement of D-dimer and COP after admission of patients to ED. D-dimer and COP were measured using the enzyme-linked immunosorbent assay (ELISA).

Statistical analysis
The collected data were entered in SPSS version 17.00 (SPSS Inc., Chicago, IL, USA). Continuous variables are presented as mean±standard deviation, and categorical variables are presented as frequency and/or percentage.
Kolmogorov-Smirnov test was also used to determine the normal distribution of continuous variables. Since the continuous variables were not normally distributed, Mann-Whitney U test was performed. Moreover, Chi-square test was performed to analyze categorical variables. The receiver operating characteristic (ROC) curve was plotted to determine the prognostic value of biomarkers. P-value less than 0.05 was considered statistically significant.

RESULTS
This study was carried out on 102 consecutive patients with suspected PTE. As shown in Table 1   Evaluation of the validity of COP test showed that it is a poorly sensitive (50%) and specific (22.9%) test. Finally, comparison of the two diagnostic criteria of COP and Ddimer showed that these two criteria did not differ significantly in terms of diagnostic value (Figure 1).   (14).
In previous studies, the prognostic and diagnostic accuracy of COP were analyzed in patients with acute coronary syndrome, heart failure, and pulmonary hypertension (15)(16)(17)(18)(19), and a strong relationship was reported between COP level and short-and long-term mortality in patients, who were referred to ED (20). In line with the present findings, some studies did not find any correlation between COP and PE, while unlike our study, some studies reported a significant relationship, and the acceptable diagnostic value of this marker was confirmed.
The cause of discrepancy between many of these studies can be primarily the small sample size. Also, the high dispersion of COP values in this study was attributed to the small sample size, and its effect on the results was significant. One of the limitations of the present study was not having two groups of subjects with and without PTE.
In the present study, suspected PTE patients were included, and after CT angiography, they were divided into two groups with and without PTE, which led to the unequal number of patients in the two groups. Since COP has a strong correlation with the severity and long-term prognosis of left ventricular heart failure, and COP level significantly increases in patients with pulmonary hypertension and right ventricular failure (21,18), it is recommended to conduct further studies regarding the diagnostic value of this marker in pulmonary patients with